1. Field of the Invention
This invention relates to a process for addition of amines to carbon-carbon double bonds, and more particularly to a process of adding amines to carbon-carbon double bonds in an enantioselective manner. The method of the invention utilizes a transition metal catalyst made from a Group 8 metal and a ligand containing one or more 2-electron donor atoms. The present invention is also directed to a colorimetric assay to evaluate potential catalysts in these reactions.
2. Brief Description of the Related Art
The metal-catalyzed addition of amines to carbon-carbon double bonds is an unsolved, synthetically important problem (Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675-703; Han, L.-B.; Tanaka, M. Chem Commun 1999, 395-402; Gasc, M. B.; Lattes, A.; Perie, J. J. Tetrahedron 1983, 39, 703-731). Recent advances have been made using lanthanide (Tian, S.; Arredondo, V. M.; Stern, C. L.; Marks, T. J. Organometallics 1999, 18, 2568-2570; Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem Soc. 1999, 121, 3633-3639; Li, Y. W.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 9295-9306) and precious metal complexes, (Coulson, D. R. Tetrahedron Lett. 1971, 429-430; Beller, M.; Trauthwein, H.; Eichberger, M.; Breindl, C.; Herwig, J.; Muller, T. E.; Thiel, O. R. Chem. Eur. J. 1999, 5, 1306-1319; Beller, M.; Trauthwein, H.; Eichberger, M.; Breindl, C.; Mxc3xcller, T., E. Eur. J. Inorg. Chem. 1999, 1121-1132; Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc. 1988, 110, 6738-6744; Dorta, R.; Egli, P.; Zurcher, F.; Togni, A. J. Am. Chem. Soc. 1997, 119, 10857-10858) but a catalyst that displays broad functional group tolerance, useful rates, and high turnover numbers for an intermolecular addition has been reported only recently. Specifically, the present inventors reported the addition of aromatic amines to both vinylarenes (Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546-9547) and dienes (Loeber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, in press), and this chemistry included asymmetric additions.
The present inventors have also been interested in developing catalysts for the addition of amines to acrylic acid derivatives. Some of these reactions can be conducted in protic solvents under relatively mild conditions without a catalyst, but some cases do occur slowly, and most examples occur slowly in aprotic solvents. Thus, one could develop enantioselective additions of amines to acrylic acid derivatives if transition metal catalysts could be found for these transformations. The products of these additions would be xcex2-amino acid derivatives that can be used in peptide analogs, or as precursors to optically active aminoalcohols, diamines, and lactams.
Lewis acids and bases catalyze the addition of azide and derivatives of hydroxylamine to substituted acrylates, and some of the catalysts provide nonracemic products in high enantiomeric excess (Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615-6616; Guerin, D. J.; Horstmann, T. E.; Miller, S. J. Org. Lett. 1999, 1, 1107; Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959). However, these catalysts are likely to be poisoned by alkyl- and arylamine reagents. Trogler reported the addition of anilinium salts to acrylonitrile catalyzed by palladium alkyl complexes ligated by either the PCP ligand (t-Bu)2P(CH2)2CH(CH2)2P(t-Bu)2 or the chelating phosphine Me2PCH2CH2PMe2.(Seligson, A. L.; Trogler, W. C. Organometallics 1993, 12, 744). However, this work did not extend successfully beyond acrylonitrile as Michael acceptor
Accordingly, what is needed in the art is a facile method for addition of amines to carbon-carbon double bonds under mild conditions, and catalysts to catalyze such reactions. The present invention is believed to be an answer to that need.
In one aspect, the present invention is directed to a process for addition of amines to carbon-carbon double bonds in a substrate, comprising: reacting an amine compound comprising a primary or a secondary amine with a compound containing at least one carbon-carbon double bond in the presence a transition metal catalyst and in the absence of an alkylaluminum co-catalyst under reaction conditions effective to form a product having a covalent bond between the primary or secondary amine and the one carbon atom of the former carbon-carbon double bond; wherein the reaction time is less than 40 hours, and wherein the reaction produces more than 20 moles of product per mole of said transition metal in said catalyst and consumes more than 30% of either of the amine compound or the compound containing at least one carbon-carbon double bond, and wherein the product contains at least 80% of one regioisomer, the transition metal catalyst comprising a Group 8 metal and a ligand containing one or more 2-electron donor atoms.
In another aspect, the present invention is directed to a process for enantioselective addition of amines to carbon-carbon double bonds in a substrate, comprising: reacting an amine compound comprising a primary or a secondary amine with a compound containing at least one carbon-carbon double bond in the presence a chiral and nonracemic transition metal catalyst under reaction conditions effective to form a product having a covalent bond between the primary or secondary amine and one carbon atom of the former carbon-carbon double bond; the transition metal catalyst comprising a Group 8 metal and a ligand containing one or more 2-electron donor atoms; and wherein the product is formed in greater than 20% yield, and with greater than 50% enantioselectivity.
In yet another aspect, the present invention is directed to a method for determining the activity of a catalyst useful in a reaction that adds primary or secondary amine compounds to compounds containing at least one carbon-carbon double bond, comprising: (1) reacting in a reaction vessel an amine compound comprising a primary or a secondary amine with a compound containing at least one carbon-carbon double bond in the presence a transition metal catalyst under reaction conditions effective to form a product containing a covalent bond between the primary or secondary amine and one carbon atom of the former carbon-carbon double bond, the transition metal catalyst comprising a Group 8 metal and a ligand containing one or more 2-electron donor atoms; (2) adding a calorimetric agent to the reaction vessel, the calorimetric agent reactive with the amine compound or the product; and (3) evaluating the degree of color in the reaction vessel to determine the activity of the catalyst.
These and other aspects will become apparent upon reading the following detailed description of the invention.